1. Field of the Invention
The present invention concerns a tenatoprazole salt, and more particularly a monohydrated salt of the (−) enantiomer of tenatoprazole, or S-tenatoprazole, a method for its preparation as well as its use in human or veterinary therapeutics, namely as proton pump inhibitor (PPI) to treat gastro-oesophageal reflux, digestive bleeding and dyspepsia.
2. Description of the Related Art
Different sulfoxide derivatives, and notably pyridinyl-methyl-sulfinyl benzimidazoles, have been described in the literature for their therapeutic properties allowing for their use as medicinal products presenting proton pump inhibiting properties to be envisaged, that is to say medicinal products which inhibit the secretion of gastric acid and are useful in the treatment of gastric and duodenal ulcers.
Omeprazole, or 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole described in patent EP 005.129, is one of the first known derivatives of the series of PPIs, possessing gastric acid secretion inhibiting properties, and is widely used as an anti-ulcerative in human therapeutics. Rabeprazole, pantoprazole and lansoprazole can also be found among the other known derivatives of pyridinyl-methyl-sulfinyl-benzimidazoles with a similar structure.
Tenatoprazole, or 5-methoxy-2-[ [(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]imidazo[4,5-b]pyridine, is described in Patent No. EP 254.588. It also belongs to the group of drugs classified under the name of “proton pump inhibitors” (PPIs), and can be used for the treatment of conditions such as gastro-oesophageal reflux, digestive bleeding and dyspepsia.
These sulfoxides have an asymmetry at the level of the sulphur atom, and can therefore generally take the form of a mixture (racemic mixture or racemate) of two enantiomers or of one or the other enantiomer. These enantiomers can classically be used under the form of salts, such as magnesium, potassium or sodium salts, which are generally easier to handle than the bases.
Patent EP 652.872 describes the magnesium salt of esomeprazole, (−) enantiomer of omeprazole, as well as a method for its preparation, the separation of the diastereo-isomers and the solvolysis in an alkaline solution. The enantioselective preparation of the (−) enantiomer of omeprazole or of its sodium salts, by oxidation of the corresponding sulphide by a hydroperoxide in the presence of a titanium complex and a chiral ligand is described in U.S. Pat. No. 5,948,789. The method described in this patent produces a mixture enriched in one or the other of the (−) and (+) enantiomers, according to the ligand used.
Different formulations have been proposed in order to improve the properties or the activity of PPIs. In the case of omeprazole, for example, PCT application WO 01.28558 describes a stable liquid formulation obtained by forming the sodium or potassium salts in situ in solution in polyethylene glycol, by action of a hydroxide on omeprazole. The medicinal product thus formulated can be used in the usual indications of PPIs.